Abstract
Abstract Endometrial cancer is the most common gynecological cancer. Estrogen-dependent endometrioid carcinoma is the most common type of endometrial cancer. In previous studies, we have identified mitogen-inducible gene 6 (Mig-6) as a downstream target of Progesterone Receptor (Pgr) action in the uterus. Ablation of Mig-6 in the murine uterus leads to the development of endometrial hyperplasia and estrogen-induced endometrial cancer. These results suggest that Mig-6 act as a tumor suppressor in endometrial cancer. To assess the effects of the overexpression Mig-6 and the PTEN/PI3K/AKT signaling pathways on uterine tumorigenesis, mice with Pten floxed (Ptenf/f) and LoxP-STOP-LoxP Mig-6 (R26Mig-6LSL) were bred to the PRCre mouse model to generate ablation of Pten and overexpression of Mig-6 in the uterus (PRcre+ R26Mig-6LSL Ptenf/f). PRcre+ R26Mig-6LSL Ptenf/f showed significantly increased survival time compared to PRcre/+ Ptenf/f mice. Double mutant mice showed significantly decreased uterine weight compared to PRcre/+Ptenf/f at 3 months of age. Gross morphology at 3 months of age showed that double mutant mice dramatically retarded the development of endometrial cancer compared to ablation of Pten alone. Histological analysis showed that endometrial adenocarcinoma with invasion into the myometrium was observed in the PRcre/+Ptenf/f mice at 3 months of age. However, double mutant mice did not develop endometrial cancer. Immunohistochemstry analysis showed significantly increased apoptosis and decreased proliferation at epithelial cells in PRcre+ R26Mig-6LSL Ptenf/f mice compared to PRcre/+ Ptenf/f mice at 3 months of age. The expression of pERK1/2 was significantly decreased in PRcre+ R26Mig-6LSL Ptenf/f mice compared to PRcre/+ Ptenf/f mice at 2 and 3 months of age. The expression of Pgr and its tartget genes was significantly increased in PRcre+ R26Mig-6LSL Ptenf/f mice compare to PRcre/+ Ptenf/f mice. However, the expression of Estrogen Receptor ≤ (Esr1) and its target genes was significantly decreased. The ability of Mig-6 to repress cancer development indicates that it exerts a tumor suppressor function in endometrial cancer. These results will contribute to the understanding of the molecular mechanism of tumorigenesis and to the development of therapeutic approaches for endometrial cancer.(Supported by NIH, R01 HD057873) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4182. doi:1538-7445.AM2012-4182
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